The basic mechanisms by which several psychopharmacological agents alter behavior in man are not well understood. Lysergic acid diethylamide, serotonin, mescaline, bufotenine and harmine were shown by the principal investigator to affect neuromuscular activity and metabolism of the liver fluke, Fasciola hepatica. There is a high degree of correlation between the psychomimetic potencies of lysergic acid derivatives in man and their neuromuscular effects in the flukes. The basic philosophy of this project is that the more we know about the biochemical effects of these agents in systems lower than mammals, such as the liver fluke, the better will be our chance to understand the effects of these agents in man as well as the mechanisms involved in psychosis. Our basic approach is to study the effect of psychopharmacological agents in the liver fluke and to compare these effects with homologous systems in the mammalian brain or other tissues. We plan to study the mechanism of activation of adenylatecyclase in the fluke by serotonin, LSD and other agents; to isolate and purify the catalytic and the hormonal components of the system. We intend to isolate the LSD - serotonin receptor(s) from the flukes, to study the nature of interaction between different psychopharmacological agents and these receptors and to study the physio-chemical properties of the receptors. The phosphorylating system that is activated by serotonin will be studied. The nature of the natural protein substrate(s) that are phosphorylated will be investigated. Phosphodiesterase will be characterized and purified and the nature of inhibition of the methyl xanthine derivatives will be examined. Studies on the biochemical and molecular properties of chemotaxis in Physarum polycephalumand the effect of psychopharmacological agents on this process will be carried out. The role of cAMP in chemotaxis and the effect of phosphodiesterase inhibitors and other psychopharmacological agents on the cyclase system will be examined.